Our research interest is to elucidate mechanisms of TGF-beta regulation of mucosal and systemic T cell immunity and tolerance, in order to offer targets to manipulate T cell immunity versus tolerance in animal models to develop potential therapies for relevant human diseases such as autoimmunity, cancer and infectious diseases. Specifically we would like to understand (1) how TGF-beta is involved in the function and development of CD4+CD25+ T regulatory cells (Treg) in mucosal and other lymphoid tissues, (2) how TGF-beta regulates T programmed cell death and the consequent immune tolerance, and (3) how TGF-beta signal transduction and TGF-beta production in mucosal T cells are regulated. Recently, we have focused on the isolation and characterization of CD4+CD25+ T regulatory cells from normal and genetically engineered mice and dissected the involvement of TGF-beta in immunosuppression mediated by T regulatory cells. Importantly, we have also identified that TGF-beta is a critical factor in the conversion of naive CD4+CD25- peripheral T cells to CD4+CD25+ T regulatory cells through induction of Foxp3, a master gene for T regulatory cell development. This finding not only has significant impact on understanding the generation of CD4+CD25+ regulatory T cells, but also makes it possible for the first time to design strategies to embellish the limited and/or inadequate numbers of T regulatory cells in the periphery, as needed, for therapeutic intervention in autoimmune diseases and inflammation. Our immediate next steps are to decipher the molecular pathway(s) by which TGF-beta induces Foxp3 expression to define how CD4+CD25+ T cells are developed in and out of mucosal lymphoid systems as well as to begin to resolve the mystery of TGF-beta's role in T regulatory cell mediated immune tolerance. We also intend to apply the knowledge obtained from our basic research to manipulate T cell immunity versus tolerance in animal models to develop potential therapy for relevant human diseases, with special attention to NIDCR mission relevant diseases, such as Sjogren?s syndrome and oral and head and neck cancers.